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2009 Grants - Ho

Physiological Function of APP Proteins in the Adult Mammalian Brain

Angela Ho, Ph.D.
Boston University
Boston, Massachusetts

2009 Investigator-Initiated Research Grant

Amyloid precursor protein (APP) is a focus of Alzheimer research because it is the precursor to the protein fragment beta-amyloid, which aggregates into amyloid plaque, a characteristic feature of Alzheimer pathology. Although the pathologic role of APP is intensively studied, its role in normal cell function is not well understood. Attempts to study the function of APP have been hampered by the fact that it has not been possible to breed experimental animals lacking the APP gene.

Angela Ho, Ph.D. and colleagues have proposed to study the normal function of APP using a new approach. They have developed a method that allows them to remove the APP gene from specific cells in the brain, rather than the entire animal. The technique relies on a unique genetic sequence called loxP that is placed on both sides of the APP gene. When an enzyme called Cre encounters the loxP sequences, it removes the APP gene and reassembles the remaining DNA. Dr. Ho's team has created mice with the loxP sequences in place. They now plan to cross these mice with another strain that expresses the Cre enzyme in specific nerve cells in two regions of the brain known as the forebrain and the hippocampus. The resulting strain of mice should be lacking the APP gene in those same nerve cells.

Dr. Ho and colleagues plan to use this new strain to examine how removal of the APP gene affects brain anatomy, biochemistry and function. They will also use similar molecular techniques to study the biochemical pathways affected by removal of APP in nerve cells growing in cell culture. These studies will advance our understanding of the normal role of APP, and perhaps provide clues to its central role in the development of Alzheimer pathology.